Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis

被引：116

作者：

Peng, Zhen-Wei ^{[1
,2
]}

Ikenaga, Naoki ^{[2
]}

Liu, Susan B. ^{[2
]}

Sverdlov, Deanna Y. ^{[2
]}

Vaid, Kahini A. ^{[2
]}

Dixit, Richa ^{[2
]}

Weinreb, Paul H. ^{[3
]}

Violette, Shelia ^{[3
]}

Sheppard, Dean ^{[4
]}

Schuppan, Detlef ^{[5
,6
]}

Popov, Yury ^{[2
]}

机构：

[1] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Oncol, Guangzhou 510275, Guangdong, Peoples R China

[2] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Gastroenterol & Hepatol, Boston, MA 02115 USA

[3] Biogen Inc, Cambridge, MA USA

[4] Univ Calif San Francisco, Sch Med, Lung Biol Ctr, San Francisco, CA USA

[5] Univ Med Ctr, Inst Translat Immunol, Mainz, Germany

[6] Univ Med Ctr, Res Ctr Immune Therapy, Mainz, Germany

来源：

HEPATOLOGY | 2016年 / 63卷 / 01期

基金：

中国国家自然科学基金;

关键词：

GROWTH-FACTOR-BETA; BILIARY FIBROSIS; STEM-CELLS; HEPATOCELLULAR-CARCINOMA; SCLEROSING CHOLANGITIS; LIVER-REGENERATION; MOUSE MODEL; SUBUNIT; PROGRESSION; ACTIVATION;

D O I：

10.1002/hep.28274

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Integrin v6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGF1). In human liver cirrhosis, v6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that v6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin v6-dependent TGF1 activation. Freshly isolated v6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by v6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-v6 antibody is recapitulated by TGF1 neutralization and rescued by addition of bioactive TGF1. Genetic disruption or selective targeting of v6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction. Conclusion: These results suggest that v6 is a promising target for chronic fibrotic liver diseases and associated cancers. (Hepatology 2016;63:217-232)

引用

页码：217 / 232

页数：16

共 50 条

[1]

BREUSS JM, 1995, J CELL SCI, V108, P2241

[2]

RESTRICTED DISTRIBUTION OF INTEGRIN BETA-6 MESSENGER-RNA IN PRIMATE EPITHELIAL TISSUES [J].